ABSTRACT
BACKGROUND: Cancer is the leading cause of death in the current decade. With the advancement in scientific technologies various treatments had been introduced but they suffer from numerous side effects. The root cause of cancer is alteration in the cell cycle which generates cancerous cells. Development of new lead which specifically target cancerous cells is needed to reduce the side effect and to overcome multidrug resistance. OBJECTIVE: Design and development of anticancer leads targeting colchicine site of microtubules using structurally screened phytofragments is the primary objective of this work. MATERIALS AND METHODS: Bioactive fragments of phytoconstituents were identified from a large dataset of phytochemicals. The identified phytofragments were used to design structures which were screened for virtual interactions with colchicine site of microtubules. Selected set of designed molecules was further screened for drug like properties and toxicity. The designed molecules which surpassed virtual filters were synthesized, characterized and further screened for anticancer potential against HEPG2 liver cancer cell line. RESULTS: A novel series of chalcones was designed by phytofragment based drug design. Synthesized compounds showed profound anticancer activity comparable to standard, 5-fluoro uracil. In the present communication, rational development of anticancer leads targeting colchicine site of microtubules has been done by integrating pocket modeling and virtual screening with synthesis and biological screening. CONCLUSION: In this present work, we found that compounds S4 and S3 showed specific interaction with colchicine site of microtubules and desirable anticancer activity. Further optimization of the lead could yield drug like candidate with reduced side effects and may overcome multidrug resistance.
Subject(s)
Antineoplastic Agents/pharmacology , Chalcones/pharmacology , Drug Development/methods , Liver Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Chalcones/chemistry , Colchicine/pharmacology , Drug Design , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Fluorouracil/pharmacology , Hep G2 Cells , Humans , Liver Neoplasms/pathology , Microtubules/drug effects , Phytochemicals/chemistry , Phytochemicals/pharmacology , Structure-Activity RelationshipABSTRACT
Dogs were subjected to a standardized hemorrhagic shock procedure. Some were treated with verapamil and others were untreated. It was found that the dogs treated with verapamil were protected from the damaging effects of hemorrhagic shock on the heart. This was true even in treated dogs that had a rapid heart rate maintained by means of an intracardiac pacing electrode. In addition, the treated dogs did not show the intestinal hemorrhage that is usually seen in dogs subjected to hemorrhagic shock. Finally, it was found that verapamil treatment increased the survival rate of shocked dogs in comparison with control dogs which were not treated.